TUMOR BIOLOGY AND MICROENVIRONMENT PROGRAM: SUMMARY The Tumor Biology and Microenvironment (TBM) Program investigates cell-autonomous processes that underlie signaling pathways and cancer stemness as well as tumor cell-extrinsic mechanisms by which stromal niche factors and immune components modulate malignancy. Members pursue studies of novel immunotherapies and other stromal targeted therapeutics (e.g. neuronal cells), and incorporate new findings and innovative approaches such as 3D organoid cultures for translation to pre-clinical applications and development of early-stage clinical trials. The TBM program is led by Michael Shen, PhD, Timothy Wang, MD, and Charles Drake, MD, PhD who have complementary scientific expertise. They direct a program with 49 members who have been collectively responsible for $16.4M of cancer-focused peer-reviewed funding in 2019, as well as 800 publications, of which 251 publications in journals with an impact factor >10 in the current funding period. During the project period, there were 486 accruals to clinical trials, of which 235 were investigator-initiated, and 139 corresponded to underrepresented minority patients. The TBM Program pursues three interrelated Specific Aims: (1) Investigation of tissue stem/progenitor cells and cancer cell stemness to identify molecular mechanisms that drive tumor malignancy and plasticity, and to identify strategies to target these processes; (2) Analysis of the tumor microenvironment to understand how stromal- epithelial cell interactions and components of the stem cell niche can modulate tumor growth; and (3) Investigation of tumor immunology and immunotherapy to elucidate the interaction of immune cells with cancer stem cells and the mechanisms that underlie the resistance of tumors to immunotherapy. In particular, the TBM Program addresses research relevant for the catchment area by focusing on prostate cancer in African-American men, as well as studies of triple-negative breast and pancreatic cancers. The TBM Program fosters the growth of Members through meetings and retreats, development funds, support of multi-investigator grant proposals, support through Shared Resources, strategic faculty recruitments, and interactions with the other HICCC Programs. The TBM Program also provides leadership in cancer research career enhancement through mentorship of early-stage researchers through training grants, fellowships and career development awards. Future goals of the TBM program include support for strategic recruitments of senior and junior faculty (areas of therapies that target the interactions of cancer stem cells and the tumor microenvironment), increased clinical trials in the area of immunotherapy including overcoming nodes of resistance, and development of inter- programmatic platforms for precision oncology.